Psychosomatics 45:371-377, October 2004
© 2004 The Academy of Psychosomatic Medicine
Tricyclic Antidepressants, QT Interval Prolongation, and Torsade de Pointes
W. Victor R. Vieweg, M.D., and
Mark A. Wood, M.D.
Received April 8, 2003; revision received Aug. 11, 2003; accepted Oct. 17, 2003. From the Department of Psychiatry and the Department of Internal Medicine, Cardiology Division, Medical College of Virginia, Virginia Commonwealth University. Address reprint requests to Dr. Vieweg, Department of Psychiatry, MCV/VCU, 17 Runswick Dr., Richmond, VA 23238-5414; vvieweg{at}vcu.edu (e-mail).
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ABSTRACT
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The authors postulate mechanisms linking tricyclic antidepressants, QT interval prolongation, torsade de pointes, and sudden cardiac death. Case reports identify amitriptyline and maprotiline as the tricyclic antidepressants most likely to provoke torsade de pointes. Risk factors of family history of congenital long QT syndrome, age, female sex, metabolic and cardiovascular disease, metabolic inhibitors, hypokalemia, drug overdose, and co-prescription of drugs associated with QT interval prolongation were found in cases of torsade de pointes associated with tricyclic antidepressants. Clinicians should be cautious when prescribing tricyclic antidepressants with other drugs, such as thioridazine, that are capable of prolonging the QT interval.
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INTRODUCTION
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By 1991, it was apparent that sodium-channel-blocking (quinidine-like) antiarrhythmic drugs were more likely to decrease than to enhance survival after myocardial infarction.1,2 By association, imipramine, which has quinidine-like properties, was linked to these findings. At that time, tricyclic antidepressants were challenged by selective serotonin reuptake inhibitors as the antidepressant drugs of choice for treatment of depression. The question of whether tricyclic antidepressants are capable of generating arrhythmias, such as torsade de pointes, de novo has not been answered. The purpose of this article is to review data implicating tricyclic antidepressants in QT interval prolongation, torsade de pointes, and sudden cardiac death. We use the label tricyclic antidepressant broadly to include heterocyclic antidepressants.
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Tricyclic Antidepressants in Cardiac Patients
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Frequent premature ventricular contractions (PVCs) are well-known markers for sudden death after myocardial infarction. Drugs suppressing PVC formation offered the hope of reducing postinfarction morbidity and mortality. The National Heart, Lung, and Blood Institute funded the Cardiac Arrhythmia Pilot Study (CAPS)3 to test the hypothesis that suppressing ventricular arrhythmias after myocardial infarction would reduce cardiac morbidity and mortality. The antiarrhythmic drugs tested in CAPS had the following sequence of efficacy in reducing postinfarction PVCs: flecainide (83% reduction in PVCs), encainide (79%), moricizine (66%), imipramine (52%), and placebo (37%). Imipramine was the least well tolerated of the antiarrhythmics used in CAPS.
CAPS set the stage for the Cardiac Arrhythmia Suppression Trial (CAST).4 CAST tested the hypothesis that suppression of postinfarction PVCs would decrease the incidence of cardiac arrest and arrhythmic death. Imipramine was not used in CAST because of the high rate of intolerable adverse effects associated with the drug. At the 1-year point, 95% of the subjects who received placebo were alive, compared with 90% of the subjects who received the active drug (p=0.0006). Also at 1 year, 96% of the subjects who received placebo, compared with 93% of the active-drug-treated subjects had not experienced cardiac arrest or arrhythmic death (p=0.003). The authors concluded that even though the antiarrhythmics employed in CAST suppressed asymptomatic or mildly symptomatic ventricular arrhythmias, these agents did not improve survival and actually increased mortality.
Stimulated by the CAST findings, Morganroth and Goin1 conducted a meta-analysis of four randomized, double-blind, active-drug-controlled parallel trials that included 1,009 subjects, of whom 502 received quinidine, 141 received flecainide, 246 mexiletine, 67 tocainide, and 53 propafenone. The authors found that the risk of dying among quinidine-treated patients was significantly greater than among subjects receiving the other four antiarrhythmic agents.
In 1993, based on the observations described earlier, Glassman et al.5 challenged their previously held belief that depressed patients with preexisting ventricular arrhythmias would benefit from tricyclic antidepressant administration both in terms of improved mood state and arrhythmia suppression. They stated that tricyclic antidepressants have class I antiarrhythmic action similar to quinidine and moricizine and, therefore, might be problematic in treating depressed patients with a wide range of cardiovascular problems. Glassman et al.5 focused on the effects of sodium-channel-blocking properties of tricyclic antidepressants.
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Tricyclic Antidepressants and Torsade de Pointes
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Figure 1 depicts the typical ECG pattern associated with torsades de pointes. Assessing the relationship between tricyclic antidepressants and torsade de pointes is largely dependent on reviewing case reports. We assessed this relationship by using PubMed links for torsade de pointes and tricyclic antidepressants, literature reviews on this topic, and our own extensive personal files.
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FIGURE 1. ECG Showing Pattern Associated With Torsade de Pointesa
aThe figure shows the typical ECG features of short-long-short RR intervals followed by the torsade de pointes type of polymorphic ventricular tachycardia. A sinus beat with normal ventricular complex [1] is followed by a premature ventricular contraction (PVC) [2] with a short coupling interval. After a long pause (long refractory period), a sinus beat [3] is followed by another PVC [4] with a short coupling interval. The second PVC [4] is the first beat of a polymorphic ventricular tachycardia consistent with torsade de pointes. P indicates the "P" wave, which represents atrial depolarization.
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No tricyclic antidepressant was noted in Darpo's6 list of the 20 drugs most commonly reported to the World Health Organization between 1983 and 1999 in association with torsade de pointes. De Ponti et al.7 provided an encyclopedic review of nonantiarrhythmic drugs associated with QT interval prolongation and torsade de pointes. They reviewed the effects of the tricyclic antidepressants amitriptyline, clomipramine, desipramine, doxepin, imipramine, maprotiline, nortriptyline, and protriptyline. Structurally, maprotiline is a tetracyclic antidepressant because it has an ethylene bridge, although it behaves like a tricyclic antidepressant in its quinidine-like properties.8–10
Table 1 summarizes several case reports linking tricyclic antidepressants with torsade de pointes.11–23 Amitriptyline and maprotiline were the agents most commonly associated with this polymorphic ventricular tachycardia. Of the 13 citations included in Table 1, five described patients who received either amitriptyline or cyclobenzaprine, a medication that is structurally almost identical to amitriptyline. Curtis et al.19 referred to another case report of amitriptyline-induced torsade de pointes. However, that report24 did not include enough details to be useful for our review.
Maprotiline has been less commercially successful than amitriptyline, and yet it was as common as amitriptyline in our series. However, drawing conclusions about the frequency of drug-induced torsade de pointes from a series of case reports is problematic. The greatest QTc interval prolongations were seen in patients receiving maprotiline.
Particularly striking was the high proportion of the case reports that described women (12 of 13 cases summarized in Table 1). Risk factors for QT interval prolongation and torsade de pointes were commonly present in the 13 cases. These risk factors included family history of congenital long QT syndrome, age, female sex, metabolic and cardiovascular disease, metabolic inhibitors, hypokalemia, drug overdose, and co-prescription of drugs associated with QT interval prolongation.25
Only one case report involved a child. In a systematic literature review of the cardiovascular effects of therapeutic doses of tricyclic antidepressants in children and adolescents, Wilens et al.26 reported no cases of torsade de pointes. Chronic medical conditions, tricyclic antidepressant overdose, and co-administration of drugs prolonging the QTc interval occur less frequently among children than adults. Thus, the sodium (fast-channel)-blocking properties of tricyclic antidepressants rather than their potassium-blocking (IKr-blocking) properties appear to dominate the cardiovascular electrophysiologic effects of these antidepressants in children.
Tricyclic antidepressants act primarily on sodium (fast) channels but also on delayed rectifier potassium (IKr) channels.27–29 The sodium-channel-blocking effects of tricyclic antidepressants may diminish the effect of IKr blockade on the QT interval. Antipsychotic drugs of the phenothiazine family (as well as other antipsychotic agents) act primarily on delayed rectifier potassium channels.30 Thus, the secondary effects of tricyclic antidepressants and the primary effects of thioridazine-like drugs may be additive. Thioridazine and several tricyclic antidepressants are primarily metabolized by the CYP450 2D6 isoenzyme.31–33 Thus, when these agents are co-administered, there is the potential for one agent to inhibit the metabolism of the other, thereby increasing the risk of torsade de pointes.
In five of the 13 cases of tricyclic antidepressant-induced torsade de pointes, QRS duration measurements were available. In three of those five cases,11,17,22 the QRS durations were normal. In only two of the 13 cases summarized in Table 1 was the QRS duration abnormally long. This finding suggests that tricyclic antidepressants' capacity to block sodium (fast) channels cannot be the only mechanism explaining QT interval prolongation. These case reports support the hypothesis that tricyclic antidepressants also block potassium channels.
Risk factors for torsade de pointes have been identified among patients taking antipsychotic drugs.34 These same risk factors apply to patients taking tricyclic antidepressants. Table 2 outlines these risk factors.
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Co-Administration of Tricyclic Antidepressants and Thioridazine-like Drugs
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Mehtonen et al.35 surveyed cases of sudden death in subjects taking antipsychotic or antidepressant drugs. The authors looked at medicolegal autopsies done in Finland during the 3-year period 1985–1988. In a database of 24,158 cases, they found 49 sudden cardiac deaths (31 women [mean age=44 years] and 18 men [mean age=40 years]) associated with the use of antipsychotic or antidepressant drugs.
A therapeutic dose of low-potency phenothiazines was present in 46 of the 49 cases, and thioridazine was involved in more than one-half of these 46 cases. Thioridazine was the only antipsychotic drug administered in 15 of the cases. Other antipsychotic or antidepressant drugs were associated with sudden cardiac death in only five cases. Even after correcting for frequency of drug use in the general population, the use of low-potency phenothiazines, particularly thioridazine, was overrepresented in these cases. There were no cases of tricyclic antidepressants used alone in this study. Subjects in nine of the 49 cases received tricyclic antidepressants. In eight of the nine cases, phenothiazines with or without a second antipsychotic drug from another class were coadministered with a tricyclic antidepressant. In one instance, a tricyclic antidepressant was prescribed with an anxiolytic but not an antipsychotic drug.
In a study of QTc interval abnormalities and psychotropic drugs, Reilly et al.36 found that 8% of the psychotropic drug users had QTc interval measurements two standard deviations greater than the mean for the normal comparison subjects. Among subjects taking both tricyclic antidepressants and antipsychotic drugs, this figure rose to 15%. Robust risk factors included age and use of tricyclic antidepressants, thioridazine, or droperidol. The QT interval comprises the combination of ventricular depolarization (QRS complex) and ventricular repolarization (from the end of the QRS complex to the end of the T wave—JT interval). For the patients taking tricyclic antidepressants and antipsychotic drugs, the authors did not comment on the extent to which increased QRS duration (ventricular depolarization) and JT interval lengthening (ventricular repolarization) contributed to QTc interval prolongation.
In one case report,23 droperidol was co-prescribed with the tricyclic antidepressant-like drug cyclobenzaprine,37 leading to further lengthening of the QTc interval and torsade de pointes. In another case of torsade de pointes, maprotiline was co-prescribed with thioridazine.19 In that case, the authors neither reported QRS duration nor considered thioridazine to be a contributory factor.
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Brugada Syndrome
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Brugada syndrome, which occurs in 0.05 to 0.1 percent of the population (more than three times the prevalence of congenital long-QT syndrome), has been discussed as a clinical entity in the cardiology literature over the past decade.38 This arrhythmic syndrome is characterized by an electrocardiographic pattern of right bundle branch block and ST segment elevation in the right precordial leads and normal QTc interval coupled with sudden death due to primary ventricular tachyarrhythmias, including torsade de pointes.39 Ventricular fibrillation is the most common documented terminal arrhythmia.38,39 Patients with Brugada syndrome are typically Caucasian or Asian men.38,39
About 20% of patients with Brugada syndrome have gene mutations located on the SCN5A gene. This genetic defect is very different from that found in congenital long QT syndrome, type 3 (LQT3), even though the gene mutation associated with that disorder is also located on the SCN5A gene.40,41 A defect in sodium (fast-channel) current contributes to reduced density of the sodium current. Administration of sodium-channel-blocking agents further reduces the density of the sodium current, leading to ventricular tachyarrhythmias.38,39
A report of tricyclic antidepressant-induced Brugada syndrome42 prompted Goldgran-Toledano et al.43 to review their experience in 98 consecutive cases of tricyclic antidepressant overdose (95 patients). For 15 patients, the authors noted electrocardiographic findings consistent with the Brugada syndrome (definite evidence for 12 patients and equivocal evidence for three patients). Among the 98 cases, the overall mortality rate was 3%. Among patients with Brugada syndrome, the mortality rate was 6.7%.
Rouleau et al.44 describe three cases of psychotropic drug-induced Brugada syndrome. In the first case, electrocardiographic changes consistent with Brugada syndrome occurred during the co-administration of a phenothiazine and amitriptyline. The second case involved fluoxetine, and the third case involved co-administration of trifluoperazine and loxapine.
Babaliaros and Hurst45 described a patient who developed Brugada syndrome during the administration of increasing doses of desipramine. The authors speculated that tricyclic antidepressant-induced Brugada syndrome is an important cause of sudden cardiac death associated with tricyclic antidepressant administration. Consequently, tricyclic antidepressants should be used judiciously in patients with heart disease and in elderly patients, and such patients should be carefully monitored by means of ECG for the development of Brugada syndrome.
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CONCLUSIONS
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Tricyclic antidepressants are less commonly associated with torsade de pointes than are antipsychotic drugs, particularly low-dose phenothiazine agents. However, there are enough case reports of tricyclic antidepressant-induced torsade de pointes to justify physicians' concern, particularly in cases of tricyclic antidepressant overdose. It seems likely that potassium-channel blockade best explains the capacity of tricyclic antidepressants to prolong the QT interval and provoke torsade de pointes. Use of a combination of tricyclic antidepressants and low-dose phenothiazines (and, perhaps, other antipsychotic drugs) may place the patient at increased risk for torsade de pointes. As is the case with antipsychotic drugs, factors such as age, sex, drug dose, co-prescription of metabolic inhibitors, hypokalemia, hypomagnesemia, metabolic and cardiovascular disease, personal history of syncope, family history of sudden cardiac death, and QTc interval prolongation are probably risk factors for tricyclic antidepressant-induced torsade de pointes.
The recent emergence of Brugada syndrome and associated torsade de pointes and sudden cardiac death apparently exacerbated by tricyclic antidepressant administration raises new concerns in psychopharmacology. More information will be necessary to place this syndrome into proper perspective for the psychiatrist.
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W. R. Zemrak and G. A. Kenna
Association of antipsychotic and antidepressant drugs with Q-T interval prolongation
Am. J. Health Syst. Pharm.,
June 1, 2008;
65(11):
1029 - 1038.
[Abstract]
[Full Text]
[PDF]
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ABSTRACT
INTRODUCTION
